School of Medicine, Tongji University, Shanghai, China.
Department of Endocrine and Metabolic Diseases/ Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Exp Cell Res. 2022 Nov 1;420(1):113336. doi: 10.1016/j.yexcr.2022.113336. Epub 2022 Sep 1.
Elevated hepatic gluconeogenesis is a major contributor of fasting hyperglycemia in diabetes. MicroRNAs (miRNAs) are tightly linked to glucose metabolism, but their role in hepatic gluconeogenesis remains largely unkown. In this current study, miR-34a-5p expression was significantly increased in liver tissues of db/db mice. Overexpression of miR-34a-5p promoted hepatic glucose production in mouse primary hepatocytes with increased expressions of gluconeogenic genes while miR-34a-5p inhibition displayed a contrary action. MiR-34a-5p overexpression in mouse primary hepatocytes repressed SIRT1 expression. SIRT1 inhibition by EX527 blocked phosphoenolpyruvate carboxykinase (PEPCK) protein degradation and enhanced hepatic gluconeogenesis. Treatment of A485 (a CBP/p300 inhibitor) decreased miR-34a-5p and PEPCK expressions in the livers of db/db mice, but elevated SIRT1 protein expression. In mouse primary hepatocytes, A485 exhibited a similar result. Overexpression of miR-34a-5p attenuated A485-inhibited gluconeogenic gene expressions and A485-induced SIRT1 protein expression. Finally, after miR-34a-5p was inhibited in the livers of db/db mice, hepatic glucose production and gluconeogenic gene expressions were markedly lowered. Our findings highlight a critical role of miR-34a-5p in the regulation of hepatic gluconeogenesis and miR-34a-5p may be a potential target in the treatment of type 2 diabetes.
肝糖异生升高是糖尿病空腹高血糖的主要原因。microRNAs (miRNAs) 与葡萄糖代谢密切相关，但它们在肝糖异生中的作用在很大程度上尚不清楚。在本研究中，miR-34a-5p 在 db/db 小鼠的肝组织中表达显著增加。miR-34a-5p 的过表达促进了小鼠原代肝细胞的肝葡萄糖生成，同时增加了糖异生基因的表达，而 miR-34a-5p 的抑制则表现出相反的作用。miR-34a-5p 在小鼠原代肝细胞中的过表达抑制了 SIRT1 的表达。EX527 抑制 SIRT1 可阻止磷酸烯醇丙酮酸羧激酶 (PEPCK) 蛋白降解并增强肝糖异生。A485（一种 CBP/p300 抑制剂）处理降低了 db/db 小鼠肝脏中的 miR-34a-5p 和 PEPCK 表达，但增加了 SIRT1 蛋白表达。在小鼠原代肝细胞中，A485 也表现出类似的结果。miR-34a-5p 的过表达减弱了 A485 抑制的糖异生基因表达和 A485 诱导的 SIRT1 蛋白表达。最后，在 db/db 小鼠肝脏中抑制 miR-34a-5p 后，肝葡萄糖生成和糖异生基因表达明显降低。我们的研究结果强调了 miR-34a-5p 在调节肝糖异生中的关键作用，miR-34a-5p 可能是治疗 2 型糖尿病的潜在靶点。
